Cell therapy in heart failure: what's up? The routine practice of skin and bone marrow transplantation provides the best illustration that cells can have a therapeutic effect. Attempts have thus be made to exploit this effect for the treatment of heart failure with the initial objective of physically replacing dead cardiomyocytes by new exogenously-supplied cells even though there has been a recent paradigm shift whereby the primary mechanism of action is rather attributed to the cell-derived secretion of factors that would harness endogenous repair pathways. The first wave of clinical trials, which have used cells from various sources, have failed to convincingly demonstrate improved outcomes but these studies have generated data that should now be leveraged for optimizing the efficacy of the technique through the selection of the most functionally efficacious cells, their combination with biomaterials and the development of delivery modalities ensuring an improved initial retention of the cellular graft. Confirmation that the primary mechanism of action is paracrine signaling possible paves the way for an a-cellular cell therapy whereby only secretion products would be administered to the patient while the role of cells would be limited to their in vitro production.